Aging is a major risk factor for a number of debilitating conditions, including heart disease, cancer, and Alzheimer's disease. This makes the need for anti-aging therapies all the more urgent. Researchers at the Salk Institute have developed a new gene therapy to help slow the aging process.
The results, published on February 18, 2019 in the newspaper Nature Medicine, highlight a new CRISPR / Cas9 genome editing that can suppress the accelerated aging observed in mice with Hickinson-Gilford syndrome, a rare genetic disorder that also affects humans. This treatment provides important information on the molecular pathways involved in accelerated aging, as well as on the reduction of toxic proteins by gene therapy.
"Aging is a complex process in which cells begin to lose their functionality, so it is essential for us to find effective ways to study the molecular factors of aging," says Juan Carlos Izpisua Belmonte, a professor at the Laboratory for Disease Control. Expression of Salk and senior author. paper. "Progeria is an ideal aging model because it allows us to quickly design, refine and test an intervention."
With an early onset and rapid progression, progeria is one of the most serious forms of a group of degenerative disorders caused by a mutation in the LMNA gene. Mice and humans with progeria have many signs of aging, including DNA damage, cardiac dysfunction and a significantly reduced life span. The LMNA gene normally produces two similar proteins within a cell: coverslip A and coverslip C. Progeria shifts the production of coverslip A to progerin. Progerine is an abbreviated and toxic form of film A that accumulates with age and is exacerbated in people with progeria.
"Our goal was to reduce the toxicity of the LMNA gene mutation that leads to an accumulation of progerin in the cell," said co-lead author Hsin-Kai Liao, a researcher at Izpisua Belmonte's laboratory. "We thought that progeria could be treated with targeted Lamin A and CRISPR / Cas9 targeted progerin disruption."
Researchers used the CRISPR / Cas9 system to deliver gene therapy in cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) containing two synthetic guide RNAs and a reporter gene was injected. The RNA guide guides the Cas9 protein to a specific location in the DNA where it can make a nick that makes the lamine A and progerin non-functional, without disrupting the lamine C. The reporter helps the researchers to follow tissues infected with AAV.
Two months after the delivery of the treatment, the mice were stronger and more active, with improved cardiovascular health. They showed a decrease in the degeneration of an important arterial blood vessel and a delayed onset of bradycardia (abnormally slow heart rate), two problems commonly seen in elderly patients and those with progeria. Overall, treated progeria mice exhibited a level of activity similar to that of normal mice and their lifespan increased by approximately 25%.
"Once we have improved the efficiency of our viruses to infect a wide range of tissues, we are confident that we will be able to increase our lifespan," said Pradeep Reddy, a postdoctoral fellow at Izpisua Belmonte Laboratory and author of the document .
Taken together, the results suggest that targeting of laminamine A and progerin using a CRISPR / Cas9 system can significantly improve the physiological health and lifespan of progeria mice. These results provide a significant new understanding of how scientists might eventually be able to target the molecular factors of aging in humans.
Future efforts will focus on making therapy more effective and refine it for human use. At present, there is no curative treatment for progeria; the symptoms are managed and the complications treated as they occur.
"This is the first time that gene modification therapy has been applied to treat progeria syndrome," said Roger Guillemin Chair Izpisua Belmonte. "This will require some improvements, but it will have much less negative effects compared to the other options available.This is an exciting step forward for the treatment of progeria."
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